A blocking of blood clotting is required in most patients requiring an extracorporeal blood purification. The contact of blood or plasma, respectively, to foreign surfaces leads to contact activation and subsequently to clotting, release of quinines and to the activation of the complement system. These processes are also triggered by extracorporeal blood purification methods, because plasma or blood, respectively, in the context of these methods is brought into contact with membranes and possibly with adsorber materials. Due to the high demands on patient safety and the high prevalence for blood-purifying therapies, a safe, effective and easily manageable anti-coagulation is essential.
In the clinical treatment of hemodialysis patients, heparin, which is introduced into the arterial branch of the extracorporeal blood circuit by means of infusion, is used as current standard. Heparin, however, can lead to complications, such as, e.g., HIT (Heparin Induced Thrombocytopenia), [Hetzel G R, Sucker C (2005), Nephrol Dial Transplant, 20 (10): 2036-2042; M. Franchini (2005), Thrombosis Journal, 3 (14)], heparin bond to the adsorber or filter or an undesired intracorporeal anti-coagulation, wherein the latter can become problematic in particular in the case of patients having an increased risk of bleeding.
The anti-coagulation with citrate [Janssen M] et al. (1993), Nephrol Dial Transplant, 8 (11): 1228-1233; Pinnick et al. (1983), N Engl J Med, Vol. 308, 258-261] represents an alternative to the heparin method. The anti-coagulatory effect of the citrate is based on the complex formation thereof with free bivalent cations, such as calcium ions and magnesium ions. Ionized calcium is an important cofactor in the clotting system, because it has a catalytic effect on most of the enzymes of the clotting cascade. A complexation of the calcium ions by means of citrate thus leads to a prevention of the development of the clotting cascade. Used concentrations reach from 2 to 7.4 mmol citrate per liter of blood [Palsson R, Niles J L (1999), Kidney Int 55: 1991-1997; Böhler et al. (1996), J Am Soc of Nephrol. 7(2), 234-241], wherein concentrations of the ionized calcium are specified from 0.25 mmol/l to 0.35 mmol/l as target values [Kutsogiannis et al. (2000), Am J Kidney Dis, Vol. 35, 802-811; Tolwani et al. (2001), Kidney International, Vol. 60, 370-374] or <0.4 mmol/l [Swartz et al. (2004), Clinical Nephrology, Vol. 61(2), 134-14], respectively, as target values.
An extracorporeal blood circuit substantially consists of a filter unit, a blood inflow from the patient to the filter unit (arterial branch) and a blood discharge from the filter unit to the patient (venous branch). The blood is pumped through the circuit by means of a blood pump. As described below, the blood flow [ml/min] is an important parameter for the system and represents the blood volume, which is pumped by the blood pump per time unit. The filter unit typically includes a dialysis filter, a plasma filter or a hemofilter, respectively, or a combination thereof. The membrane blood purification methods are based on the physical processes of diffusion and convection. A semi-permeable membrane, which separates the blood from the dialysis liquid, is located in the dialysis filter. Low-molecular substances thereby diffuse from the blood into the dialysis liquid and are thus removed from the blood. The extent of the removal of the substances is called clearance and is a function of the dialysis filter as well as of the blood and dialysis flow. In the case of dialysis, liquid accumulated in the body can also be removed from the patient by means of transmembrane pressure. This process is also called ultrafiltration. In the case of the hemofiltration, filtrate is pressed out at an ultrafiltration membrane and is replaced by substitution solution. Depending on the used filter, the filtrate includes low-molecular or low- and high-molecular substances. In the case of a further known blood purification method, filtrate is pressed out via a hemo- or plasmafilter and is recirculated in a plasma circuit, is cleaned (e.g. by means of adsorbers or by means of MDS—Microspheres Detoxification System [EP 0776223, U.S. Pat. No. 5,855,782] and is subsequently returned into the extracorporeal blood circuit. In addition to the membrane blood purification systems, there are adsorption systems, in the case of which the blood or the plasma passes through an adsorber and is cleaned by means of physicochemical processes. Typically, an adsorber consists of an active matrix, which specifically removes undesired blood components from the blood. It goes without saying that the citrate anti-coagulation is also suitable for adsorber systems. However, a dialysis filter is advantageously arranged downstream from the adsorber circuit so as to partially remove the citrate from the blood circuit prior to the reinfusion of the blood, as will be described below.
The citrate supply takes place by means of an infusion into the arterial branch of the extracorporeal blood circuit. The blood, which is blocked from clotting in such a manner, is cleaned in membrane or membrane/adsorption-based systems, respectively. The citrate as well as the citrate-calcium complex is again removed for the most part from the extracorporeal blood circuit by means of the dialysis as a function of the used dialysis filter, so that only a small portion of the infused citrate reaches into the blood circuit of the patient. A dialysis unit is thus advantageous for the citrate anti-coagulation. Citrate is metabolized to CO2 and water in the human body, wherein the citrate impact on the patient may not considerably exceed the metabolic rate, so as to prevent a patho-physiologically relevant impact on the acid-base balance. So as not to change the clotting system and other physiological functions of calcium and magnesium ions in the patient, a substitution of these ions is necessary. A calcium-containing or a calcium and magnesium-containing substitution medium is thereby introduced into the blood either by infusion into the venous branch of the extracorporeal blood circuit or via a separate vein access.
The most important therapeutic advantage of the citrate anti-coagulation lies in that—contrary to the heparin anti-coagulation—the blood clotting is exclusively blocked in the extracorporeal circuit and undesired intracorporeal bleedings are thus avoided. In addition to the anti-coagulation, a citrate addition considerably improves the biocompatibility of an extracorporeal blood purification system, because the complement activation, which requires the presence of free calcium and magnesium ions, is suppressed by the complexation of these ions. The citrate anti-coagulation can further be used in patients, in the case of whom heparin anti-coagulation is contraindicated (HIT). Due to extended filter lives in response to the use of citrate anti-coagulation, this is particularly suitable for long-term treatments, such as in the acute dialysis, e.g.
Even though the advantages of the citrate anti-coagulation as compared to the heparin standard method are obvious, it is only rarely used in the clinical treatment and only in a few blood purification devices. The following reasons explain why the method has not yet prevailed despite of its advantages for the patient: on the one hand, the citrate anti-coagulation is slightly more extensive than the heparin method and, on the other hand, it is associated with a safety risk due to the complexity of the metering and the lack of automation and standardization, it requires a careful monitoring and is thus consequently only carried out by experienced experts. In response to changes to the extracorporeal blood flow, the supply rates for citrate and for the substitution medium must be adapted manually. An incorrect metering, which is caused, for example, by means of an operating error, an incorrect adjustment of the supply rates or an infusion pump breakdown, can lead to complications, such a hypocalcaemia. This is a state, which can take on life-threatening extents. The metering should be adjusted by means of the detected ion concentration of the patient blood—advantageously of the calcium ion concentration. The risk of an undesired unphysiological state can be minimized and the safety of the patient can be ensured only by means of the most accurate as well as highly close-meshed or continuous measuring of the calcium ion concentration of the blood, which causes a likewise close-meshed or continuous adaptation of the metering of the infusion solutions. In consideration of the necessity for an anti-coagulation system, which is also suitable for patients, for whom a use of the heparin method is disadvantageous or not possible, and in consideration of the advancing aging of the population and the increasing prevalence for blood-purifying therapies connected thereto, there is thus a large demand for a reliable and effective as well as automated and standardized citrate anti-coagulation system, by means of which the patient safety can be kept as high as possible.
WO 91/06326 presents a dialysis method with citrate anti-coagulation for the use in hemodialysis. The citrate is infused into the arterial branch of the extracorporeal blood circuit, wherein the citrate supply rate is adjusted as a function of the blood flow rate. Calcium ions are substituted via a separate venous access, wherein the supply rate of the Ca-ion substitution solution is adjusted by means of the citrate supply rate and of the Ca-ion concentration of drawn blood samples detected over time intervals lasting for several hours. A close-meshed or continuous monitoring of the Ca-ion concentration, respectively, does not take place in the method described in WO 91/06326 and as already specified above, the safety of the patient can thus not be ensured completely. In addition, the lack of standardization and automation is highly limiting for the patient safety and for a user-friendly application of the system.
A device as well as a method for the citrate anti-coagulated extracorporeal blood purification can be found in US 2007/066928 A1. The document discloses a means for detecting an ion concentration, which, among others, measures bivalent cations, such as calcium and magnesium ions, and which is arranged downstream from the dialysis unit in the extracorporeal blood circuit. The metering of citrate-containing solutions, which can be infused into the extracorporeal blood circuit upstream of and downstream from the dialysis unit, is regulated as a function of the measured ion concentration. The metering of the calcium and magnesium-containing electrolyte solution takes place independent on the measured ion concentration. First and foremost, the disadvantage of the device or of the method shown in US 2007/066928, respectively, is that it is not possible to draw a conclusion to the intracorporeal physiological state of the patient. Complications, such as hypocalcaemia due to an incorrect metering of the citrate or the electrolyte solution, respectively, cannot be recognized in due time. The patient safety can thus not be completely ensured.
A further device as well as a method for the citrate anti-coagulated blood purification is shown in US 2004/133145A1. The infusion rates for the citrate and for the substitution medium are adjusted as a function of measured flow rates. In the case of this device or this method, respectively, the patient safety can also not be completely ensured.
US 2007/0007184 A1 discloses an extracorporeal blood purification system, however without citrate anti-coagulation system. The blood purification system encompasses a disposable sensor, by means of which calcium can also be measured, among others. A further device as well as method for the extracorporeal blood purification without citrate anti-coagulation is disclosed in EP 1 175 917.
DE 101 14 283 C2 discloses a method for detecting the ion concentration of the blood of a patient in the case of the citrate anti-coagulated hemodialysis and/or hemofiltration of the afore-mentioned type. Preferably, the ions are calcium and/or magnesium ions, wherein calcium ions are preferably determined.
FIG. 1 shows a device, which is suitable for these purposes and which has also become known from DE 101 14 283 C2. The device encompasses a hemodialyzer and/or hemofilter 101 as well as an extracorporeal blood circuit 102, which includes an arterial inflow 103 (arterial branch) from the patient to the hemodialyzer and/or hemofilter 101 and a venous discharge 104 (venous branch) from the hemodialyzer and/or hemofilter 101 to the patient. A citrate supply device 105 is located in the inflow 103 and a substitution medium supply device 106 is located in the discharge 104. The device furthermore has a dialysate line 107, which in turn encompasses a dialysate inflow 108 and a dialysate discharge 109. In this method, the ion concentration of the blood is determined indirectly by means of the ion concentration in the dialysate discharge 109. For this purpose, at least one means for detecting an ion concentration 110, which can be an ion-sensitive sensor, e.g., is located in the dialysate discharge 109. This means for detecting an ion concentration 110 is connected to a regulating unit as well as to the supply devices for citrate and/or for the substitution medium. To be able to determine the ion concentration of the blood by means of the method described in DE 101 14 283 C2, the ions in the dialysate must be present in non-complexated form. One possibility is a temporary interruption of the citrate infusion into the blood circuit. The other possibility is the release of the ion from the ion-citrate complex, for example by changing the pH-value by infusing acid 111 into the dialysate discharge 109 upstream of the means for detecting an ion concentration 110.
The large advantage of the method of DE 101 14 283 C2 is that access into the blood-sided portion of the extracorporeal tube system is not necessary for detecting the ion concentration of the blood. This faces the following disadvantages. As already mentioned above, a determination of the ion concentration of the patient blood, which is very close-meshed and advantageously continuous as well as as accurate as possible, is necessary for a progress of the citrate anti-coagulation, which ensures the safety. A brief interruption of the citrate addition for determining the ion concentration of the blood according to the one approach described in DE 101 14 283 C2 accordingly provides only for a discontinuous monitoring of the ion concentration and consequently for a discontinuous control of the anti-coagulation. Even in response to a brief interruption of the citrate supply, it cannot be ensured completely that a sufficient anti-coagulation can be ensured.
In the event that the ion concentration of the blood is detected via the ion concentration of the dialysate by releasing the ion from the ion-citrate complex according to the other approach in DE 101 14 283 C2, an interruption of the citrate supply is not necessary. Highly limiting for this embodiment is the relatively large effort and, above all, the difficulty of more accurately determining the ion concentration of the blood, because this is utterly impossible due to the low clearance of the ion-citrate complex as compared to free ions and a possibly incomplete release of the complexated ions. An inaccurate determination of the ion concentration thus holds the large risk of an incorrect metering of the infusion solution. To determine the ion concentration of the blood by means of the concentration in the dialysate, the blood and dialysate flow must be included according to the method disclosed in DE 101 14 283 C2, because the dialysate flow during the treatment is typically greater than the blood flow and the ion concentration of the blood thus does not correspond to the ion concentration of the dialysate. The determination of the ion concentration of the blood can either be carried out mathematically, which, however, does not allow for an accurate determination, or advantageously—because only then is it possible to make a more accurate determination—by means of reducing the dialysate flow and an accompanying adaptation of the ion concentration of the dialysate to the ion concentration of the blood. A decrease of the dialysate flow, however, involves the disadvantage that the dialysis effectiveness during this time is lowered. In the case of certain patient groups, e.g. patients having liver diseases, there is a risk of an intracorporeal citrate accumulation when the dialysate flow and thus also the effective citrate clearance are reduced in response to continuous citrate infusion. A decrease of the dialysate flow furthermore extends the duration of the dialysis for the patient and, from an economical point of view, leads to an increased use of resources. An accurate and simultaneously very close-meshed or advantageously continuous determination of the ion concentration of the blood can thus not be carried out with the method in DE 101 14 283 C2 in response to a continuously running dialysis. In addition, an automation and standardization of the citrate anti-coagulation is difficult due to the complexity of the system.
In summary, the current problems of the citrate anti-coagulation cannot be solved to a satisfactory degree with the above-cited state of the art in response to the clinical application.